The Estrogen Receptor variants β2 and β5 Induce Stem Cell Characteristics and Chemotherapy Resistance in Prostate Cancer through activation of Hypoxic Signaling

Chemotherapy resistant prostate cancer is a major clinical problem. When the prostate cancer has become androgen deprivation resistant, one of the few treatment regimens left is chemotherapy. There is a strong connection between a cancer’s stem cell like characteristics and drug resistance. By performing RNA-seq we observed several factors associated with stem cells being strongly up-regulated by the estrogen receptor β variants, β2 and β5. In addition, most of these factors were also up-regulated by hypoxia. One mechanism of chemotherapy resistance was expression of the hypoxia-regulated, drug transporter genes, where especially ABCG2 and MDR1 were shown to be expressed in recurrent prostate cancer and to cause chemotherapy resistance by efficiently transporting drugs like docetaxel out of the cells. Another mechanism was expression of the hypoxia-regulated notch3 gene, which causes chemotherapy resistance in urothelial carcinoma, although the mechanism is unknown. It is well known that hypoxic signaling is involved in increasing chemotherapy resistance. Regulation of the hypoxic factors, HIF-1α and HIF-2α is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor β variants, estrogen receptor β2 and β5, bind to and stabilize both HIF-1α and HIF-2α proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor β variants, β2 and β5, could be involved in development of a cancer’s stem cell characteristics and chemotherapy resistance, indicating that targeting these factors could prevent or reverse chemotherapy resistance and cancer stem cell expansion.

化疗耐药性前列腺癌是临床面临的重大难题。当前列腺腺癌进展为雄激素剥夺抵抗时，剩余的有效治疗方案之一即为化疗。癌症干细胞（cancer stem cell）样特征与药物耐药性之间存在紧密关联。通过RNA测序（RNA-seq），我们观察到雌激素受体β（estrogen receptor β）的两种亚型β2与β5可显著上调多种干细胞相关因子。此外，多数此类因子亦可被缺氧环境上调。化疗耐药的潜在机制之一为缺氧调控的药物转运基因的表达：其中ABCG2与MDR1已被证实可在复发性前列腺癌中表达，并通过高效将多西他赛（docetaxel）等药物泵出细胞而介导化疗耐药。另一机制为缺氧调控的Notch3基因的表达，该基因已被证实可在尿路上皮癌中引发化疗耐药，但其具体分子机制尚未明确。众所周知，缺氧信号通路可参与增强化疗耐药性。缺氧诱导因子-1α（HIF-1α）与缺氧诱导因子-2α（HIF-2α）的调控机制极为复杂，远不止缺氧本身。我们近期的研究表明，雌激素受体β的两种亚型β2与β5可结合并稳定HIF-1α及HIF-2α蛋白，进而诱导缺氧诱导因子靶基因的表达。本研究提示，雌激素受体β亚型β2与β5的表达上调可能参与癌症干细胞样特征的形成与化疗耐药的发生，这表明靶向此类因子或可预防或逆转化疗耐药，并抑制癌症干细胞的扩增。